PROJECT SUMMARY In this project, we will study Burmese pythons (BPs), a natural paradigm of rapid, massive, controlled and recurring organ growth. Several studies have shown that unlike laboratory mammals and humans, the BPs naturally feed infrequently, and their feeding habits are associated with rapid and massive regulatory responses and organ growth, which is followed by a postdigestion regression phase. This unique model can provide valuable insights about the underlying adaptive, beneficial, well-orchestrated growth and regression cellular regulatory programs and how they differ from the uncontrolled processes of cancer and the various maladaptive hypertrophic or atrophic disease states. In the proposed studies, we hope to develop a deeper mechanistic understanding specifically about intestinal adaptation. By studying the growth phase in the immediate post-feeding period, we can discover those mechanisms that drive the gut and the other organs so efficiently and rapidly from dormancy to full function. The analysis of the regression phase will provide us with valuable information about the mechanisms, which may act as a ?brake? and halt growth. This project builds upon and expands our preliminary comparative studies of rodents, pythons and humans, which have revealed conserved intestinal signatures and key regulatory networks. Comparative studies between species are powerful and the discovery of common, evolutionary conserved mechanistic targets, processes and pathways provide further confidence on the significance of the findings. The differences may represent opportunities to harness, for therapeutic benefits by trying to recapitulate in mammals, for example, the transcriptomic patterns that are different in BPs. Our data highlight the role of microRNAs (miRNAs), which are small non-coding RNAs that regulate gene expression at the post-transcriptional level. They are excellent candidates for mediating the plasticity of the intestinal adaptive processes, as they are master regulators of gut homeostasis and many functions. In addition, because miRNAs can be secreted in the circulation, they are ideally suited to serve as a mode of communication between the gut and distal tissues. In the first specific aim, we seek to define a signature of dynamically regulated miRNAs that parallels the growth and regression of the intestine in BPs and mice. In the second specific aim, we will develop a high-resolution cellular atlas of the intestinal transcriptomic changes that are associated with the growth-regression cycles in BPs. We propose a novel, transformative project that brings together cutting-edge technologies, a team of multidisciplinary investigators and a fascinating new animal model system, which could shift current research paradigms and expand current research models, because of the numerous scientific and practical advantages it offers. It will enable and set the foundations for further mechanistic studies, while it will generate unique information, resources and valuable datasets. We anticipate that the interest in this model will grow, given the recent developments (e.g., annotation of the genome), its increasingly appreciated advantages and the interest by the lay public.